A randomised double-blind placebo-controlled trial of minocycline and/or omega-3 fatty acids added to treatment as usual for at risk Mental States: The NAYAB study.

BACKGROUND: Inflammatory mechanisms are thought to contribute to the onset of psychosis in persons with an at-risk mental state (ARMS). We investigated whether the anti-inflammatory properties of minocycline and omega-3 polyunsaturated fatty acids (omega-3), alone or synergistically, would prevent transition to psychosis in ARMS in a randomised, double-blind, placebo-controlled trial in Pakistan. METHODS: 10,173 help-seeking individuals aged 16-35 years were screened using the Prodromal Questionaire-16. Individuals scoring 6 and over were interviewed using the Comprehensive Assessment of At-Risk Mental States (CAARMS) to confirm ARMS. Participants (n = 326) were randomised to minocycline, omega-3, combined minocycline and omega-3 or to double placebo for 6 months. The primary outcome was transition to psychosis at 12 months. FINDINGS: Forty-five (13.8 %) participants transitioned to psychosis. The risk of transition was greater in those randomised to omega-3 alone or in combination with minocycline (17.3.%), compared to 10.4 % in those not exposed to omega-3; a risk-ratio (RR) of 1.67, 95 % CI [0.95, 2.92] p = 0.07. The RR for transitions on minocycline vs. no minocycline was 0.86, 95 % CI [0.50, 1.49] p > 0.10. In participants who did not become psychotic, CAARMS and depression symptom scores were reduced at six and twelve months (mean CAARMS difference = 1.43; 95 % CI [0.33, 1.76] p < 0.01 in those exposed to omega-3. Minocycline did not affect CAARMS or depression scores. INTERPRETATION: In keeping with other studies, omega-3 appears to have beneficial effects on ARMS and mood symptom severity but it increased transition to psychosis, which may reflect metabolic or developmental consequences of chronic poor nutrition in the population. Transition to psychosis was too rare to reveal a preventative effect of minocycline but minocycline did not improve symptom severity. ARMS symptom severity and transition to psychosis appear to have distinct pathogeneses which are differentially modulated by omega-3 supplementation. FUNDING: The study was funded by the Stanley Research Medical Institute.

A culturally adapted manual-assisted problem-solving intervention (CMAP) for adults with a history of self-harm: a multi-centre randomised controlled trial.

BACKGROUND: Self-harm is an important predictor of a suicide death. Culturally appropriate strategies for the prevention of self-harm and suicide are needed but the evidence is very limited from low- and middle-income countries (LMICs). This study aims to investigate the effectiveness of a culturally adapted manual-assisted problem-solving intervention (CMAP) for patients presenting after self-harm. METHODS: This was a rater-blind, multicenter randomised controlled trial. The study sites were all participating emergency departments, medical wards of general hospitals and primary care centres in Karachi, Lahore, Rawalpindi, Peshawar, and Quetta, Pakistan. Patients presenting after a self-harm episode (n = 901) to participating recruitment sites were assessed and randomised (1:1) to one of the two arms; CMAP with enhanced treatment as usual (E-TAU) or E-TAU. The intervention (CMAP) is a manual-assisted, cognitive behaviour therapy (CBT)-informed problem-focused therapy, comprising six one-to-one sessions delivered over three months. Repetition of self-harm at 12-month post-randomisation was the primary outcome and secondary outcomes included suicidal ideation, hopelessness, depression, health-related quality of life (QoL), coping resources, and level of satisfaction with service received, assessed at baseline, 3-, 6-, 9-, and 12-month post-randomisation. The trial is registered on ClinicalTrials.gov. NCT02742922 (April 2016). RESULTS: We screened 3786 patients for eligibility and 901 eligible, consented patients were randomly assigned to the CMAP plus E-TAU arm (n = 440) and E-TAU arm (N = 461). The number of self-harm repetitions for CMAP plus E-TAU was lower (n = 17) compared to the E-TAU arm (n = 23) at 12-month post-randomisation, but the difference was not statistically significant (p = 0.407). There was a statistically and clinically significant reduction in other outcomes including suicidal ideation (- 3.6 (- 4.9, - 2.4)), depression (- 7.1 (- 8.7, - 5.4)), hopelessness (- 2.6 (- 3.4, - 1.8), and improvement in health-related QoL and coping resources after completion of the intervention in the CMAP plus E-TAU arm compared to the E-TAU arm. The effect was sustained at 12-month follow-up for all the outcomes except for suicidal ideation and hopelessness. On suicidal ideation and hopelessness, participants in the intervention arm scored lower compared to the E-TAU arm but the difference was not statistically significant, though the participants in both arms were in low-risk category at 12-month follow-up. The improvement in both arms is explained by the established role of enhanced care in suicide prevention. CONCLUSIONS: Suicidal ideation is considered an important target for the prevention of suicide, therefore, CMAP intervention should be considered for inclusion in the self-harm and suicide prevention guidelines. Given the improvement in the E-TAU arm, the potential use of brief interventions such as regular contact requires further exploration.

Extracorporeal life support in mitral papillary muscle rupture: Outcome of multicenter study.

BACKGROUND: Post-acute myocardial infarction papillary muscle rupture (post-AMI PMR) may present variable clinical scenarios and degree of emergency due to result of cardiogenic shock. Veno-arterial extracorporeal life support (V-A ECLS) has been proposed to improve extremely poor pre- or postoperative conditions. Information in this respect is scarce. METHODS: From the CAUTION (meChanical complicAtion of acUte myocardial infarcTion: an InternatiOnal multiceNter cohort study) database (16 different Centers, data from 2001 to 2018), we extracted adult patients who were surgically treated for post-AMI PMR and underwent pre- or/and postoperative V-A ECLS support. The end-points of this study were in-hospital survival and ECLS complications. RESULTS: From a total of 214 post-AMI PMR patients submitted to surgery, V-A ECLS was instituted in 23 (11%) patients. The median age was 61.7 years (range 46-81 years). Preoperatively, ECLS was commenced in 10 patients (43.5%), whereas intra/postoperative in the remaining 13. The most common V-A ECLS indication was post-cardiotomy shock, followed by preoperative cardiogenic shock and cardiac arrest. The median duration of V-A ECLS was 4 days. V-A ECLS complications occurred in more than half of the patients. Overall, in-hospital mortality was 39.2% (9/23), compared to 22% (42/219) for the non-ECLS group. CONCLUSIONS: In post-AMI PMR patients, V-A ECLS was used in almost 10% of the patients either to promote bridge to surgery or as postoperative support. Further investigations are required to better evaluate a potential for increased use and its effects of V-A ECLS in such a context based on the still high perioperative mortality.

Participant Recruitment From Low- and Middle-Income Countries for Pivotal Trials of Drugs Approved by the U.S. Food and Drug Administration : A Cross-Sectional Analysis.

BACKGROUND: Many participants in clinical trials supporting U.S. Food and Drug Administration (FDA) drug approvals are recruited from outside the United States, including from low- and middle-income countries (LMICs). Where participants are recruited for pivotal trials has implications for ethical research conduct and generalizability. OBJECTIVE: To describe LMIC recruitment for pivotal trials of newly approved drugs for cancer, neurologic disease, and cardiovascular disease. DESIGN: Cross-sectional analysis. SETTING: Pivotal trials of new cancer, cardiovascular, and neurologic drugs approved from 2012 to 2019 matched to ClinicalTrials.gov, FDA records, and publications. MEASUREMENTS: Host countries and available per country enrollments were extracted. The primary end point was the proportion of pivotal trials enrolling participants in LMICs. The secondary end point was the proportion of pivotal trial participants contributed by LMICs for each indication area. RESULTS: Data were obtained from 66 new drugs and 144 pivotal clinical trials. All cardiovascular approvals (12 drugs, 29 trials) and neurologic approvals (26 drugs, 54 trials) were analyzed, as well as a random sample of cancer approvals (28 of 85 drugs [33%]) matched to their pivotal trials (61 of 210 trials [29%]). Among the trials, 56% in cancer, 79% in cardiovascular disease, and 56% in neurology recruited from an LMIC. For multicountry trials, country-level enrollment figures were not available for 71 trials (55%). For those reporting per country enrollment, the percentage of participants recruited from LMICs was 8% for cancer trials, 36% for cardiovascular trials, and 17% for neurology trials. LIMITATIONS: The study was limited to FDA-approved drugs in 3 areas, including a sample of cancer drugs. Pivotal trials of nonapproved drugs or drugs for other indications were not captured. CONCLUSION: Most pivotal trials for FDA-approved drugs recruit from LMICs. Publications and FDA documents generally do not provide country-level data on recruitment. PRIMARY FUNDING SOURCE: None.

Improvement of Metabolic and Histological Changes of Adiposity in Rats by Synthetic Oleoyl Chalcones.

We previously reported that synthetic oleoyl chalcones had a favorable effect to alleviate metabolic consequences of obesity in male SD rats. In this work, we prepared and characterized by spectroscopic tools, a set of six oleoyl chalcones (5a-c, 10 and 11a,b). The comparative effects of the previously prepared oleoyl chalcones and their new synthetic analogs on metabolic and histological changes in obese male SD rats were studied. It was found that the oleoyl chalcones IIIa and IV were the best in improving many metabolic parameters, e. g., FBG, FI, ISI, TG, and total cholesterol. They cured systemic inflammation, through inhibition of the TNF-α and induction of adiponectin production. Moreover, chalcones IIIa and IV alleviated the oxidative stress accompanying obesity through the induction of the antioxidant enzymes GPX, SOD and CAT besides, GSH. Interestingly, chalcones IIIa and IV exerted hepatoprotective potency and ameliorated the manifestations of NAFLD via inhibition of apoptosis and induction of autophagy of hepatic cells. In conclusion, the oleoyl chalcones IIIa and IV were the most effective candidates among the series of synthetic chalcones in correcting body weight and the consequent metabolic and histological changes in adiposity.

Perioperative Levels of Troponin and BNP and the Outcome after Coronary Artery Bypass Grafting.

BACKGROUND: The independent predictive values of troponin I (cTnI) and B-type natriuretic peptide (BNP) after coronary artery bypass grafting (CABG) have been reported in several studies. However, adjustment only has been limited to preoperative risk factors. AIM: This study was conducted to assess the independent values of postoperative cTnI and BNP to predict the outcome after CABG with adjustment for preoperative risk estimates and postoperative complications and to report risk stratification gains, when considering the European System for Cardiac Operative Risk Evaluation (EuroSCORE) combined with postoperative biomarkers. METHODS: This retrospective cohort study included 282 consecutive patients undergoing CABG between January 2018 and December 2021. We evaluated the preoperative and postoperative cTnI and BNP, EuroSCORE, and postoperative complications. The composite endpoint was death or cardiac-related adverse events. RESULTS: The AUROC for postoperative cTnI was significantly higher than that of BNP (0.777 vs. 0.625, p = 0.041). The optimal cut-off values to predict the composite outcome were >4830 (pg/mL) and >6.95 (ng/mL) for BNP and cTnI, respectively. Adjustment for relevant and significant perioperative factors showed that postoperative BNP and cTnI had a high discriminatory power (C-index = 0.773 and 0.895, respectively) for predicting major adverse events. CONCLUSIONS: Postoperative BNP and cTnI are independent predictors of death or major adverse events, following CABG, and can add to the predictive power of EuroSCORE II.

[Long Noncoding RNAs MEG3, TUG1, and hsa-miR-21-3p Are Potential Diagnostic Biomarkers for Coronary Artery Disease].

Peripheral blood biomarkers are of particular importance to diagnose certain diseases including coronary artery disease (CAD) due to their non-invasiveness. Investigating the expression of noncoding RNAs (ncRNAs) paves the way to early disease diagnosis, prognosis, and treatment. Consequently, in this research, we aimed to investigate a panel of ncRNAs as potential biomarkers in patients with coronary artery disease. Two different groups have been designed (control and CAD). All participants were subjected to interviews and clinical examinations. Peripheral blood samples were collected, and plasma was extracted. At the same time, target ncRNAs have been selected based on literature review and bioinformatic analysis, and later they underwent investigation using quantitative real-time PCR. The selected panel encompassed the long non-coding RNAs (lncRNAs) MEG3, TUG1, and SRA1, and one related microRNA (miRNA): hsa-miR-21-3p. We observed statistically significant upregulation in MEG3, TUG1, and hsa-miR21-3p in CAD patients compared to control participants (p-value < 0.01). Nevertheless, SRA1 exhibited downregulation with no statistical significance (p-value > 0.05). All ncRNAs under study displayed a significantly strong correlation with disease incidence, age, and smoking. Network construction revealed a strong relationship between MEG3 and TUG1. ROC analysis indicated high potentiality for hsa-miR-21-3p to be a promising biomarker for CAD. Moreover, MEG3 and TUG1 displayed distinguished diagnostic discrimination but less than hsa-miR-21-3p, all of them exhibited strong statistical significance differences between CAD and control groups. Conclusively, this research pinpointed that MEG3, TUG1, and hsa-miR-21-3p are potential biomarkers of CAD incidence and diagnosis.

Conservative management of a rare case of atrial septal hematoma after pediatric cardiac surgery.

Atrial septal hematoma is uncommon complication that may happen after any cardiac intervention. Although it is rare, it can pose a challenging situation in the postoperative care. Multiple management approaches has been described with different outcomes. Here we are reporting a boy, aged 13 years, with dilated aortic root who underwent aortic root replacement with valve preservation. Postoperative course was complicated by atrial septal hematoma. A nonsurgical management approach was chosen based on the patient clinical condition. Regression in size with complete resolution of the hematoma was observed during the follow up.

Multiple Skip Incisions Versus Single Long Incision for Single-stage Basilic Transposition Arteriovenous Fistula: A Cohort Study.

BACKGROUND: Basilic vein transposition via single long incision is a renowned technique despite its known wound-related complications. Contrary to that, multiple skip incisions technique is thought to have relatively lower wound-related complications. But to the best of our knowledge, these 2 techniques have never been formally compared. Therefore, we conducted this study to compare both. MATERIAL AND METHODS: This was a retrospective cohort study. Patients who underwent basilic vein transposition arteriovenous fistula (AVF) from January 2011 till May 2016 at Aga Khan University Hospital, Pakistan were eligible for inclusion in the study. Study population was divided into 2 groups; one group comprising of patients who underwent fistula formation through single long incision and the other group had the procedure carried out via multiple skip incisions. Wound-related complications including wound infection and dehiscence, fistula maturation time, duration of surgery, and primary patency at a follow-up of 12 months were recorded. RESULTS: Both the groups were comparable regarding baseline variables. Incidence proportion of wound infection, hematoma, and dehiscence was higher in long incision group; however, it was statistically insignificant. Primary patency at 12 months in skip versus long incision group was 73.0% vs. 69.7% (P-value: 0.62). The mean maturation time for fistula was 42.8 ± 9.5 days and 44.3 ± 10.4 days in skip and long incision group, respectively (P-value:0.31). Duration of surgery was comparable in both. CONCLUSIONS: Although skip technique does not have significant benefit over long incision technique based on these results, but it is a valid alternative. Randomized control trial is required to better differentiate between these two.

Role of Simulated Training for Carotid Endarterectomy: A Systematic Review.

Vascular surgery trainees often do not get to perform carotid endarterectomy (CEA) directly on the patients as it requires meticulous surgical technique and has a high risk of procedure-related complications. Hence, the role of simulation in training future vascular surgeons becomes essential. This review aims to assess the types and utility of simulators available for CEA. In this systematic review, all the studies performed on CEA simulation were included. The purpose of this review was to assess different types of simulators and their usefulness for CEA. We identified 122 articles, of which 10 were eligible for review. A variety of simulators, ranging from animal models, virtual reality simulators and commercially designed models with high fidelity options were used. Technical competence was the major domain assessed in the majority of the studies (n=8), whereas four studies evaluated anatomical and procedural knowledge. Blinding was done in five studies for assessment purposes. The majority of studies (n=9) found the simulation to be an effective tool for achieving technical competence. This review shows the potential usefulness of simulation in acquiring technical skills and procedural acumen for CEA. The available literature is unfortunately too diverse to have a common recommendation.

Surgical treatment for post-infarction papillary muscle rupture: a multicentre study.

OBJECTIVES: Papillary muscle rupture (PMR) is a rare but potentially fatal complication of acute myocardial infarction. The aim of this study was to analyse the patient characteristics and early outcomes of the surgical management of post-infarction PMR from an international multicentre registry. METHODS: Patients underwent surgery for post-infarction PMR between 2001 through 2019 were retrieved from database of the CAUTION study. The primary end point was in-hospital mortality. RESULTS: A total of 214 patients were included with a mean age of 66.9 (standard deviation: 10.5) years. The posteromedial papillary muscle was the most frequent rupture location (71.9%); the rupture was complete in 67.3% of patients. Mitral valve replacement was performed in 82.7% of cases. One hundred twenty-two patients (57%) had concomitant coronary artery bypass grafting. In-hospital mortality was 24.8%. Temporal trends revealed no apparent improvement in in-hospital mortality during the study period. Multivariable analysis showed that preoperative chronic kidney disfunction [odds ratio (OR): 2.62, 95% confidence interval (CI): 1.07-6.45, P = 0.036], cardiac arrest (OR: 3.99, 95% CI: 1.02-15.61, P = 0.046) and cardiopulmonary bypass duration (OR: 1.01, 95% CI: 1.00-1.02, P = 0.04) were independently associated with an increased risk of in-hospital death, whereas concomitant coronary artery bypass grafting was identified as an independent predictor of early survival (OR: 0.38, 95% CI: 0.16-0.92, P = 0.031). CONCLUSIONS: Surgical treatment for post-infarction PMR carries a high in-hospital mortality rate, which did not improve during the study period. Because concomitant coronary artery bypass grafting confers a survival benefit, this additional procedure should be performed, whenever possible, in an attempt to improve the outcome. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov: NCT03848429.

Hyperosmolar Hyperglycaemic State and Diabetic Ketoacidosis in Nivolumab-Induced Insulin-Dependent Diabetes Mellitus.

Nivolumab is a monoclonal antibody directed against programmed cell death-1 receptor. It has an increasing application in the treatment of various advanced metastatic cancers. The incidence of autoimmune side effects associated with such agents is expected to increase. New-onset autoimmune diabetes mellitus associated with immune checkpoint inhibitor treatment is rare, occurring in less than 1% of patients. Nivolumab-induced diabetes often presents as diabetic ketoacidosis, which could be life-threatening if not recognized and treated promptly. We present the case of a patient who developed severe diabetic ketoacidosis concomitant with hyperosmolar hyperglycaemic state (HHS) after receiving nivolumab for metastatic testicular lymphoma. Pre-nivolumab blood glucose levels were normal, apart from transient hyperglycaemia related to steroids as part of the chemotherapy protocol. The diagnosis was confirmed with extremely low C-peptide in the clinic. LEARNING POINTS: Checkpoint inhibitor-associated diabetes can present abruptly with life-threatening complications.Most patients require multiple daily injections of insulin upon discharge.Cessation of checkpoint inhibitor therapy does not revert diabetes.

Surgical Treatment of Postinfarction Ventricular Septal Rupture.

Importance: Ventricular septal rupture (VSR) is a rare but life-threatening mechanical complication of acute myocardial infarction associated with high mortality despite prompt treatment. Surgery represents the standard of care; however, only small single-center series or national registries are usually available in literature, whereas international multicenter investigations have been poorly carried out, therefore limiting the evidence on this topic. Objectives: To assess the clinical characteristics and early outcomes for patients who received surgery for postinfarction VSR and to identify factors independently associated with mortality. Design, Setting, and Participants: The Mechanical Complications of Acute Myocardial Infarction: an International Multicenter Cohort (CAUTION) Study is a retrospective multicenter international cohort study that includes patients who were treated surgically for mechanical complications of acute myocardial infarction. The study was conducted from January 2001 to December 2019 at 26 different centers worldwide among 475 consecutive patients who underwent surgery for postinfarction VSR. Exposures: Surgical treatment of postinfarction VSR, independent of the technique, alone or combined with other procedures (eg, coronary artery bypass grafting). Main Outcomes and Measures: The primary outcome was early mortality; secondary outcomes were postoperative complications. Results: Of the 475 patients included in the study, 290 (61.1%) were men, with a mean (SD) age of 68.5 (10.1) years. Cardiogenic shock was present in 213 patients (44.8%). Emergent or salvage surgery was performed in 212 cases (44.6%). The early mortality rate was 40.4% (192 patients), and it did not improve during the nearly 20 years considered for the study (median [IQR] yearly mortality, 41.7% [32.6%-50.0%]). Low cardiac output syndrome and multiorgan failure were the most common causes of death (low cardiac output syndrome, 70 [36.5%]; multiorgan failure, 53 [27.6%]). Recurrent VSR occurred in 59 participants (12.4%) but was not associated with mortality. Cardiogenic shock (survived: 95 [33.6%]; died, 118 [61.5%]; P < .001) and early surgery (time to surgery ≥7 days, survived: 105 [57.4%]; died, 47 [35.1%]; P < .001) were associated with lower survival. At multivariate analysis, older age (odds ratio [OR], 1.05; 95% CI, 1.02-1.08; P = .001), preoperative cardiac arrest (OR, 2.71; 95% CI, 1.18-6.27; P = .02) and percutaneous revascularization (OR, 1.63; 95% CI, 1.003-2.65; P = .048), and postoperative need for intra-aortic balloon pump (OR, 2.98; 95% CI, 1.46-6.09; P = .003) and extracorporeal membrane oxygenation (OR, 3.19; 95% CI, 1.30-7.38; P = .01) were independently associated with mortality. Conclusions and Relevance: In this study, surgical repair of postinfarction VSR was associated with a high risk of early mortality; this risk has remained unchanged during the last 2 decades. Delayed surgery seemed associated with better survival. Age, preoperative cardiac arrest and percutaneous revascularization, and postoperative need for intra-aortic balloon pump and extracorporeal membrane oxygenation were independently associated with early mortality. Further prospective studies addressing preoperative and perioperative patient management are warranted to hopefully improve the currently suboptimal outcome.

Combined modality treatment improves tumor control and overall survival in patients with early stage Hodgkin's lymphoma: a systematic review.

Combined modality treatment (CMT) of chemotherapy followed by localized radiotherapy is standard treatment for patients with early stage Hodgkin's lymphoma. However, the role of radiotherapy has been questioned recently and some clinical study groups advocate chemotherapy only for this indication. We thus performed a systematic review with meta-analysis of randomized controlled trials comparing chemotherapy alone with CMT in patients with early stage Hodgkin's lymphoma with respect to response rate, tumor control and overall survival (OS). We searched Medline, EMBASE and the Cochrane Library as well as conference proceedings from January 1980 to February 2009 for randomized controlled trials comparing chemotherapy alone versus the same chemotherapy regimen plus radiotherapy. Progression free survival and similar outcomes were analyzed together as tumor control. Effect measures used were hazard ratios for OS and tumor control as well as relative risks for complete response (CR). Meta-analyses were performed using RevMan5. Five randomized controlled trials involving 1,245 patients were included. The hazard ratio (HR) was 0.41 (95% confidence interval (CI) 0.25 to 0.66) for tumor control and 0.40 (95% CI 0.27 to 0.59) for OS for patients receiving CMT compared to chemotherapy alone. CR rates were similar between treatment groups. In sensitivity analyses another 6 trials were included that did not fulfill the inclusion criteria of our protocol but were considered relevant to the topic. These trials underlined the results of the main analysis. In conclusion, adding radiotherapy to chemotherapy improves tumor control and OS in patients with early stage Hodgkin's lymphoma.

Global assessment of national mandatory vaccination policies and consequences of non-compliance.

BACKGROUND: Declining vaccination coverage and increasing hesitancy is a worldwide concern. Many countries have implemented mandatory vaccination policies to promote vaccination. However, mandatory vaccination policies differ significantly by country. Beyond case studies, no comprehensive study has compared these policies or the penalties for non-compliance on a global scale. METHODS: We conducted extensive keyword, policy, and literature searches to identify mandatory national vaccination policies globally and develop a comprehensive database. A mandatory national vaccination policy was defined as a policy from a national authority that requires individuals to receive at least one vaccination based on age or to access a service. Two reviewers independently evaluated evidence for a mandate and whether non-compliance penalties were incorporated. We categorized penalties into four types, based on the nature of the penalty. These penalties impact an individual's financial, parental rights, educational (i.e., child's school entry and access), and liberty status. We rated the severity within each category. RESULTS: Of 193 countries investigated, 54% (n = 105) had evidence of a nationwide mandate as of December 2018. The frequency, types, and severity of penalties varied widely across all regions. We found that 59% (n = 62) of countries with national mandates defined at least one penalty for non-compliance with a vaccine mandate. Among those, educational penalties (i.e., limiting a child's entry or ongoing access to school) were the most common (69%; n = 43), with most countries with educational penalties refusing school enrollment until vaccination requirements are met (81%; n = 35). CONCLUSION: We undertook a comprehensive assessment of national mandatory vaccination policies and identified a diversity of penalties in place to promote compliance. Our results highlight the need to critically evaluate the implementation of non-compliance penalties in order to determine their effectiveness and to define best practices for sustaining high vaccination uptake worldwide.

Does education about local vaccination rates and the importance of herd immunity change US parents' concern about measles?

It is unclear how broadly aware parents are of the concept of herd immunity and whether parents consider community benefits of vaccination when making decisions about their child's vaccinations. We aimed to determine whether educating parents about community-level benefits of measles, mumps, and rubella (MMR) vaccination and local vaccination rates would impact concern about their child's risk of measles and risk of a measles outbreak. We conducted an electronic survey among Minnesota parents of children aged 6-18 years in August 2016. We assessed baseline knowledge of herd immunity, asked participants to estimate MMR vaccination coverage in their county, and asked participants to estimate the minimum coverage needed to prevent measles outbreaks. We then delivered a short, educational intervention via the survey to inform participants about the benefits of herd immunity, the actual MMR vaccination coverage in their county, and that at least 95% MMR vaccination coverage is needed to prevent measles outbreaks. Pre- and post-intervention, participants were asked to report how concerned they were that their child might get measles. We used logistic regression models to assess factors associated with awareness of herd immunity, change in concern about one's child's measles risk, and overall concern for a measles outbreak. Among 493 participants, 67.8% were aware of herd immunity at baseline. Post-intervention, 40.2% (n = 198) of parents learned that MMR vaccination rates in their county were higher than they expected. All participants found out that their county MMR rates were lower than the measles herd immunity threshold of 95%. Overall, 27.0% (n = 133) of participants reported an increase in concern that their child might get measles after learning about local vaccination coverage and the coverage needed to achieve herd immunity. We found that our short, educational intervention aimed to increase awareness about herd immunity and local vaccination led to an increase in concern about disease risk among less than a third of parents.

Minocycline and celecoxib as adjunctive treatments for bipolar depression: a multicentre, factorial design randomised controlled trial.

BACKGROUND: Several small studies suggest that the adjunctive use of anti-inflammatory agents might improve depressive symptoms in bipolar disorder. However, there are few well designed, appropriately powered clinical trials assessing the efficacy of these novel treatment strategies. We aimed to assess the efficacy of adjunctive minocycline or celecoxib in this setting. METHODS: This double-blind, 12-week, randomised, placebo-controlled trial was done in four outpatient psychiatric clinics in Pakistan. Eligible participants were adults (aged 18-65 years) with DSM-5 bipolar disorder (type I or II) and a major depressive episode. In a 2 × 2 factorial design, participants were randomly assigned (1:1:1:1) to receive either active minocycline plus active celecoxib, active minocycline plus placebo celecoxib, placebo minocycline plus active celecoxib, or placebo minocycline plus placebo celecoxib. The primary outcome was the mean change from baseline to week 12 in score on the 17-item Hamilton Depression Rating Scale (HAMD-17), assessed in all randomised participants (missing data were imputed and assumed to be missing at random). The trial was registered with ClinicalTrials.gov, NCT02703363. FINDINGS: 266 (17%) of 1542 patients assessed between May 1, 2016, and March 31, 2019, were randomly assigned to receive minocycline plus celecoxib (n=68), minocycline plus placebo (n=66), celecoxib plus placebo (n=66), or placebo plus placebo (n=66). From baseline to week 12, depressive symptoms as per HAMD-17 reduced in all four groups (from 24·5-25·2 to 11·3-12·8), but these reductions did not differ significantly between the groups. In terms of main effects, reductions in HAMD-17 did not differ for patients treated with minocycline (mean adjusted difference vs non-minocycline 1·48 [95% CI -0·41 to 3·36]; p=0·123) or for celecoxib (mean adjusted difference vs non-celecoxib -0·74 [-2·61 to 1·14]; p=0·443). Rates of serious adverse effects did not differ between groups (31 participants had a manic switch, two self-harmed, and one died in a motor vehicle accident). INTERPRETATION: We found no evidence that minocycline or celecoxib was superior to placebo for the treatment of bipolar depression. This large trial casts doubt on the potential therapeutic benefits of adjunctive anti-inflammatory drugs for the acute management of bipolar depression. FUNDING: Stanley Medical Research Institute.

Genetic variations among the isolates of Bipolaris Maydis based on phenotypic and molecular markers

Abstract Maydis leaf blight, caused by Bipolaris maydis, is an important disease of maize crop in Khyber Pakhtunkhwa (KP) Pakistan. Fifteen isolates of the pathogen, collected across KP, were studied for variability based on phenotypic and molecular markers. Significant variability among the isolates was observed when assessed using phenotypic traits such as radial growth, spore concentration, fungicide sensitivity and virulence. The isolates were classified into six culture groups based on colour, texture and margins of the colony. Conidial morphology was also variable. These were either straight or slightly curved and light to dark brown in colour. Fungicide test showed significant variation in the degree of sensitivity against Carbendazim. Isolate Bm8 exhibited maximum radial growth on carbendazim spiked plates. Conversely, isolate Bm15 showed the lowest radial growth. Variations in virulence pattern of the isolates were evident when a susceptible maize variety Azam was inoculated with spores of B. maydis. Genetic variability amongst the isolates was also estimated by RAPD as well as sequencing of ITS region. The RAPD dendrogram grouped all the isolates into two major clusters. Average genetic distance ranged from 0.6% to 100%, indicating a diverse genetic gap among the isolates. Maximum genetic distance was found between isolates Bm9 and Bm10 as well as Bm2 and Bm8. Conversely, isolates Bm13 and Bm15 were at minimum genetic distance. Phylogenetic dendrogram based on sequencing of ITS region grouped all the isolates into a single major cluster. The clusters in both the dendrogram neither correlate to the geographical distribution nor to the morphological characteristics.

Resumo A ferrugem das folhas de maydis, causada por Bipolaris maydis, é uma doença importante da cultura do milho em Khyber Pakhtunkhwa (KP), Paquistão. Quinze isolados do patógeno, coletados em KP, foram estudados quanto à variabilidade com base em marcadores fenotípicos e moleculares. Variabilidade significativa entre os isolados foi observada quando avaliada por meio de características fenotípicas, como crescimento radial, concentração de esporos, sensibilidade a fungicida e virulência. Os isolados foram classificados em seis grupos de cultura com base na cor, textura e margens da colônia. A morfologia dos conídios também foi variável. Estes eram retos ou ligeiramente curvos e de cor marrom-claro a escuro. O teste de fungicida mostrou variação significativa no grau de sensibilidade ao carbendazim. O isolado Bm8 exibiu crescimento radial máximo em placas com adição de carbendazim. Por outro lado, o isolado Bm15 apresentou o menor crescimento radial. As variações no padrão de virulência dos isolados foram evidentes quando uma variedade de milho suscetível Azam foi inoculada com esporos de B. maydis. A variabilidade genética entre os isolados também foi estimada por RAPD, bem como sequenciamento da região ITS. O dendrograma RAPD agrupou todos os isolados em dois grupos principais. A distância genética média variou de 0,6% a 100%, indicando uma lacuna genética diversa entre os isolados. A distância genética máxima foi encontrada entre os isolados Bm9 e Bm10 e também entre Bm2 e Bm8. Por outro lado, os isolados Bm13 e Bm15 estavam a uma distância genética mínima. O dendrograma filogenético baseado no sequenciamento da região ITS agrupou todos os isolados em um único aglomerado principal. Os agrupamentos em ambos os dendrogramas não se correlacionam com a distribuição geográfica nem com as características morfológicas.

Comparison of Upper Limb Translocated Femoral Vein and Prosthetic Arteriovenous Bridge Grafts.

Introduction Native veins are an ideal option for dialysis in a patient with chronic kidney disease (CKD) as compared to a prosthetic graft. Femoral vein (FV) translocation to the upper arm is also an alternative to a prosthetic graft as reported in the literature when all options of using the native veins of the arms are exhausted. Thus, we aimed to compare the patency of the upper limb translocated FV arteriovenous fistula (AVF) with a prosthetic arteriovenous bridge graft (AVBG). Methods It is a retrospective cohort study that was conducted in the Department of Vascular Surgery, Aga Khan University Hospital. It included adult patients who underwent either upper arm translocation of FV or prosthetic AVBG using the consecutive purposive sampling technique. There were a total of 10 patients who underwent FV translocation AVF and 20 patients who had AVBG in the upper arms. Results A total of 30 patients were included in the study. Of these 30 patients, 10 underwent FV translocation AVF and the remaining 20 had AVBG. There was a significant difference in the mean operating time of the two surgeries. The mean operating time in FV translocation was 223 (± 41.5) minutes and in those with AVBG, the mean operating time was 100 (±26.5) (p= <0.001). There was no significant difference in the total length of hospital stay in both procedures performed. The primary patency rate for FV translocation was 90% and 95% in AVBG (p=1.00). Ten percent of FV translocation had a primary failure rate compared with that of AVBG, which was 5% (p=1.00). The mean follow-up period was 61 weeks in the FV translocation group and 64 weeks in the AVG group. Conclusion There was no significant difference in both groups in terms of patency, length of hospital stay, and fewer complications were observed in the FV translocation group as compared with the AVBG group.

Operative Techniques to Prevent Dialysis Access-associated Steal Syndrome in High-risk Patients Undergoing Surgery for Hemodialysis Access: A Systematic Review.

Up to 10% of patients suffer from various degrees of dialysis access-associated steal syndrome (DASS) after surgery for hemodialysis access. This systematic review was conducted to find out optimal intra-operative techniques to prevent DASS in high-risk patients. This systematic review is registered with PROSPERO (2017:CRD42017060804). It was conducted at Department of Surgery, Aga Khan University Hospital, Karachi. All types of studies conducted on intra-operative techniques to prevent DASS in high-risk population (Age > 60 years, female gender, diabetes mellitus, peripheral arterial disease and previous DASS) undergoing access creation from January 1990 till April 2019 were included in the systematic review. Thorough search was conducted on Pubmed, Google Scholar and Cochrane databases to identify relevant articles. Included studies reviewed for success of various techniques to prevent dialysis access steal syndrome are summarized. Out of 125 studies in the initial search, six met the inclusion criteria. Five were retrospective case series while one was a case report. The largest study sample size was 32. All but one study had arterio-venous access creation on an arm. "Proximalization of arterial inflow" was described in three and "prophylactic distal revascularization and interval ligation (DRIL) procedure" in two studies to prevent DASS. Only one patient out of these studies developed DASS at an overall follow-up of 7-42 months. Proximalization of inflow has been reported as the most common procedure performed to prevent DASS followed by extension technique and DRIL procedure. All three procedures have satisfactory outcome with no clear superiority of one over the other.